In recent years, it has become clear that excess reactive oxygen species (ROS) are produced in living bodies due to irregular lifestyles, aging, social stress and the like, leading to a variety of chronic conditions (arteriosclerosis, diabetes, etc.) and intractable diseases (Alzheimer's, Parkinson's, etc.). Normally the oxidation-antioxidation (redox) balance is strictly regulated in vivo, but when excess ROS are produced, the balance of oxidation-antioxidation factors shifts towards oxidation. Various antioxidants have been studied in the past for preventing chronic conditions, but in the case of low-molecular-weight antioxidants, the effective dose is low because they inhibit mitochondrial electron transport and other essential reactions in the body when administered at high doses and for reasons of kidney excretion and metabolism, and these antioxidants are also problematic because they disperse through the body, causing systemic side-effects. Attempts have also been made to treat and prevent oxidative stress disease with low-molecular-weight antioxidants, but the effects have not been impressive.
Therefore, the inventors have developed a novel nanotherapy for eliminating ROS in necessary areas, using a self-assembling nanoparticle (nitroxide radical-containing nanoparticle: RNP) comprising a nitroxide radical as a catalytically functioning ROS scavenger, enclosed in a polymer chain (Patent Document 1).
Subsequently, the inventors have confirmed and disclosed in a still-unpublished patent application description that such an RNP is retained long-term in the blood vessels in the form of a nanoparticle after intravenous administration, and has a strong therapeutic effect against cerebral infarction, myocardial infarction and acute renal failure when it breaks down in tissue subject to oxidative stress.
Considering these circumstances, the inventors have developed a novel therapy for eliminating ROS in necessary areas, using a self-assembling nanoparticle enclosing a nitroxide radical as a catalytically functioning ROS scavenger (Patent Document 1). They have also provided a composition comprising such an RNP together with another drug such as a low-molecular-weight antioxidant (Patent Document 2). This document describes the use of the composition as a medicinal preparation for oral administration, but does not describe the effects of actual oral administration. Moreover, the inventors have confirmed that a cationically chargeable RNP itself or a conjugate (forming a polymer micelle in an aqueous medium) of an anionic drug encapsulated in the RNP using the property of cationic chargeability is retained long-term in the blood vessels in the form of a nanoparticle after intravenous administration, and is therapeutically effective against cerebral infarction, myocardial infarction and acute renal failure caused by oxidative stress because the micelle or particle breaks down in tissue subject to oxidative stress (see Patent Document 1 in part, and currently unpublished patent application in part).
However, in some cases the modes of use of this RNP are limited by its property of breaking down in tissue subject to oxidative stress, and by the subsequently discovered property of rapidly breaking down in acidic environments such as gastric fluid.